AIM: To evaluate glutathione transferase theta 1 and mu 1 (GSTT1 and GSTM1) polymorphisms as determinants of primary open angle glaucoma (POAG) risk, independently or in combination with cigarette smoking, hypertension and diabetes mellitus. METHODS: A case-control study with 102 POAG patients and 202 age and gender-matched controls was carried out. Multiplex-polymerase chain reaction method was used for the analysis of GSTM1 and GSTT1 polymorphisms. The differences between two groups were tested by the t-test or χ2 test. Logistic regression analysis was used for assessing the risk for disease development. RESULTS: The presence of GSTM1-null genotype did not contribute independently towards the risk of POAG. However, individuals with GSTT1-active genotype were at almost two-fold increased risk to develop glaucoma (P=0.044) which increased up to 4.36 when combined with GSTM1-null carriers (P=0.024). When glutathione transferase (GST) genotypes were analyzed in association with cigarette smoking, hypertension and diabetes, only carriers of GSTT1-active genotype had significantly increased risk of POAG development in comparison with GSTT1-null genotype individuals with no history of smoking, hypertension and diabetes, respectively (OR=3.52, P=0.003; OR=10.02, P<0.001; OR=4.53, P=0.002). CONCLUSION: The results obtained indicate that both GSTM1-null and GSTT1-active genotypes are associated with increased POAG risk among smokers, suggesting potential gene-environment interaction in glaucoma development.